Multiple randomized clinical trials have shown that delivery of higher radiation doses to the prostate results in improved tumor control rates in prostate cancer radiation therapy (RT). As local recurrence mostly occurs at the primary tumor, particularly for high-risk patients, additional dose escalation is expected to improve the treatment outcome. However, the application of dose escalation for prostate RT is greatly limited by the tolerance of nearby healthy tissues that cannot adequately be excluded from the radiation field. This limitation can be overcome by dose painting, where a higher dose is applied to the prostate tumor only instead of the whole prostate gland. Stereotactic body radiation therapy (SBRT) offers reduced treatment time, convenience, and possibly increased treatment efficacy as compared to the conventionally fraction scheme. UTSW is currently conducting a dose escalation trial using SBRT for high-risk prostate cancer patients with an integrated dose boost on MRI-visualized prostate tumor. However, prostate can move and deform during the beam delivery. To ensure the escalated dose is actually delivered to tumor regions as planned, a reliable tumor tracking method is urgently needed. While intra-prostatic tumors can be identified by multi-parametric MRI (mpMRI) for treatment planning, intrafraction tumor tracking during the beam delivery is not achievable with mpMRI. In contrast, ultrasound offers a cost-effective and real-time imaging with high soft tissue contrast. However, conventional ultrasound techniques only provide anatomic structure of the prostate gland without the capability to differentiate tumor region from the rest of the prostate gland. Temporal enhanced ultrasound (TeUS) has emerged as a new paradigm for prostate tissue characterization by analyzing the time-series ultrasound images with advanced machine learning techniques. In this project, we aim to develop, optimize and evaluate an innovative TeUS based intra-prostatic tumor tracking method to guide SBRT with an integrated dose boost for high-risk prostate cancer patients. The specific aims are: 1) Develop TeUS-based intra-prostatic tumor delineation for guiding focused dose escalation; 2) Integrate and validate TeUS-based tumor tracking system during SBRT; and 3) Evaluate clinical gain of TeUS guided SBRT for high risk prostate cancer patients. Successful completion of the proposed project will lead to the development and validation of a low-cost yet highly accurate TeUS guided system for targeted prostate cancer RT. With enhanced real-time visualization of tumor, the use of TeUS for RT guidance will lead to better treatment efficacy and reduced toxicity.